The structural and stereochemical requirements for activity within the cannabinoid group of compounds is well-established (Mechoulam and Feigenbaum, Prog. Med. Chem. 24: 159-207, 1987). Such compounds contain a tricyclic benzopyran ring system with a free phenolic group on C-3' and on alkyl side chain on C-5'. The natural active constituents of cannabis, as well as numerous synthetic analogs with cannabimimetic psychotropic activity are the stereospecific (-) enantiomers, that is the [3R,4R] configuration, of tetrahydrocannabinol (THC).
In contrast, the stereospecific (+) enantiomers, i.e. the [3S,4S] configuration of tetrahydrocannabinols, are generally devoid of cannabimimetic activity. Some of these non-psychotropic THC type compounds with [3S,4S] configuration have been shown to have considerable therapeutic potential, including antiemetic, antiglaucoma, analgesic and neuroprotective effects, as described below.
The major active constituent of cannabis is .DELTA..sup.1 THC (also named .DELTA..sup.9 THC by another nomenclature). The 1,1 dimethylheptyl (DMH) homolog of [3R,4R]-7-hydroxy .DELTA..sup.6 THC, denoted HU-210, is a superpotent agonist with cannabimimetic activity two orders of magnitude higher than the natural .DELTA..sup.1 THC (Mechoulam and Feigenbaum, Id.).
HU-211 is the (+)-(3S,4S) enantiomer of the synthetic cannabinoid 7-hydroxy-.DELTA..sup.6 -tetrahydrocannabinol 1,1-dimethylheptyl (THC-DMH). In contrast to HU-210 (the (-)-(3R,4R) THC-DMH enantiomer), HU-211 displays a very low affinity to the cannabinoid receptors and is inactive as a cannabimimetic (Devane et al., J. Med. Chem. 35: 2065-2069, 1992). Several in vitro and in vivo pharmacological studies have described HU-211 as a functional N-methyl-D-aspartate (NMDA) receptor antagonist and neuroprotective agent.
HU-211 was shown to block NMDA-induced tremor, seizures and lethality in mice. (Feigenbaum et al., Proc. Natl. Acad. Sci. U.S. 86: 9584-9587, 1989). Application of HU-211 to rat brain cortical membrane preparations blocked the increase in binding of .sup.3 H-labeled N-[1-(2-thienyl)-cyclohexyl]piperidine ([.sup.3 H]TCP) induced by polyamines, glutamate or glycine. Furthermore, HU-211 was shown to block the NMDA induced uptake of .sup.45 Ca.sup.++ ions into primary rat forebrain cell cultures suggesting that HU-211 inhibits the influx of calcium ions across the NMDA receptor linked ion channel (Nadler et al., Brain Res. in press, 1993). Administration of HU-211 to rats with closed head injury, a model of head trauma, significantly reduced the extent of edema formation and overall neurological damage (Shohami et al., J. Neurotrauma 10: 109-119, 1993). Moreover, HU-211 was shown to prevent neuronal cell damage produced in the CA1 hippocampal region in gerbils caused by common carotid artery occlusion (CCAo) when injected after the ischemic insult (Bar-Joseph et al., J. Neurochem. 61: S65A, 1993).
It has been well documented that excessive stimulation of excitatory amino acid receptors, mainly those of the NMDA receptor subtype, is closely involved in processes of central neuronal toxicity and degeneration (Choi, Neuron 1: 623-634, 1988). The therapeutic potential of excitatory amino acid antagonists has been proposed for a wide variety of acute or chronic neurological disorders (Rogawski, TIPS 14: 325-331, 1993). As an NMDA receptor antagonist, HU-211 can prevent or ameliorate excitotoxic neuronal damage associated with ischemia, anoxia and head trauma.
In the last few years, several groups of compounds which structurally cannot be looked upon as classical cannabinoids have been found to produce cannabimimetic effects, for example the compounds CP-55940 [Little et al., J.Pharmacol.Exp.Ther., 247, 1046-1051 (1988)], pravadoline [D'Ambra et al., J.Med. Chem., 35, 124-135 (1992)], and HU-250 [Mechoulam et al., J.Med. Chem. 33, 1037-1043 (1990)]. See also Mechoulam et al. U.S. Pat. No. 4,282,248.
A new family of compounds has been discovered that exhibits a pharmacological profile of activities related to that of HU-211. Unlike classical cannabinoids, these compounds lack the typical 6-membered oxygen-containing benzopyran ring. The new family of compounds may be exemplified by (+)-4-[4-DMH-2,6 diacetoxyphenyl]-2-carboxy-6,6-dimethylbicyclo[3.1.1]hept-2-en, herein denoted HU-259. The stereochemistry at C-1 is S. The protons at C-1 and C-5 are cis and at C-5 and C-4 are trans. Thus, the stereochemistry parallels that of HU-211.